1,1-Diphenyl-1{40 -phenylthio-di-propylamine and the salts thereof

ABSTRACT

The invention relates to a new thio-alkylamine of the formula:   AND ITS SALTS. THE NEW THIO-ALKYLAMINE POSSESSES PHARMACOLOGICAL PROPERTIES, ESPECIALLY ANTI-ULCER ACTIVITY. The invention also relates to a process for preparing the new thio-alkylamine and its pharmaceutical acceptable salts. The new thio-alkylamine is prepared by condensing a corresponding amine or a salt thereof with a corresponding halogenated compound or with a corresponding carbonyl compound followed by reduction. The salts of the new thio-alkylamine can also be obtained by reaction of the free base of the above formula with a pharmaceutically acceptable acid.

United States Patent 1 Bianchini et al.

[451 May 20, 1975 1,1-DIPHENYL-1 '-PHENYLTHlO-DI- PROPYLAMINE AND THE SALTS THEREOF [76] lnventors: Pietro Bianchini, Via Sagittario, 58, Modena, Italy; Eupremio Vitale, Via Murri, 153; Guido Guerra, Via Castuglione, 34; Giustino Censoni, Via Mazzini, 44, all of Bologna, Italy 22 Filed: Sept. 22, 1972 21 Appl. No.: 291,273

[56] References Cited UNITED STATES PATENTS 3,565,955 2/l97l Ehrhart etal 260/570 Primary Examiner-Robert V. Hines Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACT The invention relates to a new thio-alkylamine of the formula:

S CH CH CH NH CH CH CH Related US. Application Data [63] Continuation-in-part of Ser. No. 270,807, July 11,

1972, abandoned,

[30] Foreign Application Priority Data July 15, l97l [52] US. Cl...... 260/343.7; 260/50l.21; 260/566 F; 260/570 R; 260/570.5 S, 260/599; 260/609 R; 260/649 R; 424/280; 424/316; 424/330 [51] Int. Cl C07d 5/12 [58] Field of Search 424/330; 260/570, 501.21, 260/343.7

ltaly 3476/71 2 Claims, No Drawings 1 1,1-DIPHENYL-l-PHENYLTHIO-DI- PROPYLAMINE AND THE SALTS THEREOF This is a continuation-in-part of application Ser. No. 5 270,807, filed July ll, 1972, now abandoned.

The present invention relates to a new thioalkylaminc of the formula:

CH CH CH N'H 2 2 CH CH CH S and its salts. The new thio-alkylamine of the invention possesses valuable pharmacological properties.

The present invention also relates to a process for the preparation of the above compound and of its pharmaceutically acceptable salts. The compound of the present invention, having the above formula (I), has proven to be remarkably active in the presence of the three main kinds of experimental ulcers, shows a weak spasmolytic activity and can be usefully employed in the human therapy.

The pharmaceutically acceptable salts of the compound with the above formula (I) include salts which are formed from acids which do not increase the intrinsic toxicity of the present compound. These acids can be as well as inorganic as organic.

As inorganic acids, the following ones can be used, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, pyrophosphoric acid, sulphuric acid and nitric acid.

As organic acids, which are pharmaceutically acceptable there can be used for example acetic acid, formic acid, propionic acid, tartaric acid, malic acid, citric acid or ascorbic acid.

The compound of the above formula (I) is prepared according to the present invention by condensing an amine of the formula:

CH CH CH NH or a salt thereof with an halogenated compound of the S5 formula:

X-CH2CH2CH2-S (III) or by condensing an amine of the formula:

HZN CH2 CH2 CH2 5 (IV) or a salt thereof with a halogenated compound of the formula:

CH CH CH X wherein X represents a halogen selected from chlorine, bromine and iodine. According to still another method of the present invention the compound of formula (I) can be prepared by condensing an amine of formula (II) with a carbonyl compound of the formula:

and reducing the condensation product to the com pound (I).

The condensation of compounds (II) and (Ill) and of compounds (IV) and (V) is carried out a. by addition of the amine of formula (II) to the halogen compound of formula (III) at a temperature from 30 to C., over a period of 3 to 6 hours, preferably in solution and under an inert atmosphere, or,

b. by addition of the amine of formula (IV) to the halogen compound of formula (V) at a temperature from 30 to 100C. over a period of 3 to 6 hours, preferably in solution and under an inert atmosphere.

Both the reactions (a) and (b) are carried out in the presence of an acid binding agent which will remove the hydrohalic acid as it is formed.

After completing the reaction, the reaction mixture is kept at a temperature from 30. to 100C. over a period from 3 to 6 hours, and the reaction mixture is then allowed to stand for about 12 hours at room temperature.

After separating off the precipitate the compound of the invention is recovered from the filtrate as the free base by conventional techniques, such as concentration to a small volume, dissolution of the residue in chloroform, treatment with an acid, washing with water and making alkaline with ammonium hydroxide.

The crude product is generally obtained as a thick oil which solidifies on addition of organic solvents; the crude solid can be purified by crystallization.

As already mentioned, the above condensation reaction preferably carried out in solvents such as aliphatic alcohols, aliphatic or aromatic ethers, aliphatic or aromatic hydrocarbons e.g. methanol, ethanol, propanol, ethyleneglycol, ethyleneglycol monoalkylethers,

3 ethyleneglycol dialkylethers, anisole, ligroin, benzene and toluene.

Suitable basic agents which will remove the hydro halic acid as it is formed at the condensation reaction include for example collidine, pyridine, N,N- dimethylaniline, N,N-diethylaniline, triethylamine and quinoline.

EXAMPLE 120 g of hot 3-thiophenyl-l-bromo-propane were slowly added to a solution of 1 g of 3.3-diphenyl propylamine in isopropanol and 150 ml of triethylamine, under a stream of nitrogen.

The mixture was then refluxed for 5 hours and allowed to stand for 12 hours at room temperature.

The precipitated triethylamine hydrobromide was filtered off and the filtrate was concentrated. The oily residue was dissolved in chloroform and the solution was then saturated with gaseous hydrogen chloride and afterwards several times washed with warm water. The solution was dried over anhydrous sodium sulphate whereafter the solvent was evaporated.

The oily residue became solid on addition of a mixture 1:1 (v/v) of isopropanol and ether, whereafter the product was crystallized from isopropanol.

50 g of product were obtained, having a melting point from l15to 116C.

Analysis:

C70 H% N% Calculated for C H N Cl S 72,42 7,09 3.51 Found 72,73 7,25 3,63

( sn g/ g) WAY SEX MOUSE (Swiss) SEX RAT (Wistar) i.v. M l7,l5 F 19,70

i.p. M 39,40 F 59,72

p.0. M I 000 l" 1000 ("l Wcil & Thompson method (confidence interval lfitlflfi 2 Subacute toxicity test in the rat.

: 28 days Wistar rats Morini) of both sexes 1 50 mg/Kg so.

200 mg/Kg 0s Duration 5 Animal Dose Remarks:

Signs Mortality Food consumption Bodyweight change Urine analysis Haematology Blood Chemistry Liver Chemistry Gross pathology and organ weight analysis Histology Results:

With both tested doses no significant variations appeared in respect of the animals used for the control.

3 Prolonged toxicity test in the rat.

Duration 13 weeks Animals Wistar rats (Morini) of both sexes Dose I50 mg/Kg os Same tests as for subacute toxicity. In no cases have there been significant changes in respect of the animals used for the control.

4 Prolonged toxicity test in the rat and in the minipig Duration 26 weeks Animals Wistar rats (Morini) of both sexes 4O Doses 25-75 l50 mg/Kg 05 in the rat 500 mg/os in the mini-pig Same tests as for subacute toxicity. In no cases have there been significant changes in respect of the animals used for the control.

5 Teratology in the rat and in the rabbit.

Foetal toxicity in the rat: the compound in question has been administered orally in the dose of 100 mg/Kg for 28 days.

In both tests have taken into consideration the lowing parameters:

number of embryonic implantations and their distribution in the uterine horn number of riabsorptions number of leaving foetuses number of dead foetuses incidence, type and number of malformations foetuses weight longitudinal histological sections of the foetuses in toto scheletons of foetuses (obtained through clearing with alkalies and dyeing with Alizarin S) thigh-bones length and distribution in frequency classes The administration of the compound in exam did not modify the paramcters taken into consideration in any way.

fol

6 To examine the pharmacodynamic properties of the Continued above prepared compound, the following tests have TEST se WAY INHIBITION been carried out: s/

l Tests in vitro shay ulcer s.c. 45 Z 50 u. antispastic acitivity 5 Reserpin ulcer 20 s 4 b binding receptor drug Prednisolon ulcer 1O i m, 75 2 i Anti ulcer activity H'Smmin ulcer 50 63 100 92 Restrain ulcer s.c. 82 92 Shay ul cer Serotonin ulcer l0 s.c. 75 Reserpin ulcer 10 50 05 72.5 p d i l ulcer lndometacin ulcer 25 05 6O 50 73 lstamm ulcer 125 76 Serotonin ulcer 250 88 Glucose ulcer 50 0s 64 Indometacin ulcer Glucose ulcer 3 Analgesic & Anesthetic activity 4 Other pharmacological activities I Tests in vitro at. Anti-spastic activity:

It has been tested on sections of isolated organs of rats and guinea-pigs, in comparison with histamine, acetylcholine, serotonin, brandykinine, BaCl and 3 Analgesic and Anesthetic activity The analgesic activity has been evaluated through the following tests:

contractions induced by chemical substances clip in rats tail On both tests the product has resulted inactive. The anesthetic activity has been studied through the followoxytocyne. in tests In the following table are shown the percentage inhibig annulment of corneous palpebral reflex 1n the rabtions and relevant ED bit infiltration anesthesia in guinea-pig. TESTS 10% T5 10% EDM In the first test, the compound of the example has resulted far more active than lydocaine, used as compara- Ach. 68.0 84.0 22.0 2 10:: tive drug, at the same concentration (1%). S 33': '28 18 In the second test of the example activity resulted BK 69.0 17.0 3 10- equal to that of lydocaine (0.1%). 5 HT inhibition in function of the contact time other pharmacological activities OXlT contractions increase Dextran edema At 10 mg/Kg and mg/Kg doses administered respectively s.c. and orally, the compound inhibits in the b. Binding receptor-drug: range of 50% the forming of edema in rats paw. Duration of occupation time of receptor compart- Intestinal peristalsis ments by the compound has been determined mea- No changes of motility and intestinal transit. suring the length of anti-serotoninic action in vitro. What we claim is: 2 Anti-ulcer activity 1. Compound of the formula:

H c I CH 0 2 H2 in CH2 c1 CH2 s Such activity, evaluated through tests by different and its pharmaceutically acceptable salts. mechanism of action, is resumed in the following table: 2. Pharmaceutically acceptable salts of the compound according to claim 1 selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric TEST Dose WAY 'NHIBITION acid, metaphosphoric acid, pyrophosphoric acid, sulmg/Kg phunc acid, nitric acid, acetic acid, formic acid, propanoic acid, tartaric acid, malic acid, citric acid or ascor- R a 5 5l es rain ulcer 10 F, 58 60 blC aCld. 

1. A COMPOUND OF THE FORMULA:
 2. Pharmaceutically acceptable salts of the compound according to claim 1 selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, pyrophosphoric acid, sulphuric acid, nitric acid, acetic acid, formic acid, propanoic acid, tartaric acid, malic acid, citric acid or ascorbic acid. 